tbuckley/cabot-search huggingface dataset:
Definitions and Standardized Endpoints for Treatment of Coronary Bifurcations
Authors: Mattia Lunardi, Yves Louvard, Thierry Lefèvre, Goran Stankovic, Francesco Burzotta, Ghassan S. Kassab, Jens F. Lassen, Olivier Darremont, Scot Garg, Bon-Kwon Koo, Niels R. Holm, Thomas W. Johnson, Manuel Pan, Yiannis S. Chatzizisis, Adrian Banning, Alaide Chieffo, Dariusz Dudek, David Hildick-Smith, Jérome Garot, Timothy D. Henry, George Dangas, Gregg W. Stone, Mitchell W. Krucoff, Donald Cutlip, Roxana Mehran, William Wijns, Faisal Sharif, Patrick W. Serruys, Yoshinobu Onuma
Journal: Journal of the American College of Cardiology (2022)

The Bifurcation Academic Research Consortium (Bif-ARC) project originated from the need to overcome the paucity of standardization and comparability between studies involving bifurcation coronary lesions. This document is the result of a collaborative effort between academic research organizations and the most renowned interventional cardiology societies focused on bifurcation lesions in Europe, the United States, and Asia. This consensus provides standardized definitions for bifurcation lesions; the criteria to judge the side branch relevance; the procedural, mechanistic, and clinical endpoints for every type of bifurcation study; and the follow-up methods. Considering the complexity of bifurcation lesions and their evaluation, detailed instructions and technical aspects for site and core laboratory analysis of bifurcation lesions are also reported. The recommendations included within this consensus will facilitate pooled analyses and the effective comparison of data in the future, improving the clinical relevance of trials in bifurcation lesions, and the quality of care in this subset of patients.
Abstract A020: Multi-species regulatory analysis of osteosarcoma to reduce clinical trial failure rates
Authors: Tina Salehi Torabi, Soumya Gottipati, Tamer Kahveci, Kiley Graim
Journal: Cancer Research (2022)

Abstract Osteosarcoma is a rare pediatric cancer characterized by poor prognosis and a high likelihood of metastasis, for which no systemic treatments have been successfully developed in the past 30 years [1]. The lack of effective biologically relevant osteosarcoma tumor models is a significant obstacle to the development of effective therapeutics [2]. Therefore, developing a framework that addresses this issue is essential in further advancing therapeutics studies. We postulate that a comparative genomics approach, evaluating whole-transcriptome osteosarcoma response in species closely related to humans, would highlight immune and other differences in each species that will better guide the design of human therapeutics. To investigate this, we compile RNA-seq data from studies of mice, human, and canine osteosarcoma [3], and perform an integrated analysis of disease in these three species. We build a tri-species multi-layer network of regulatory interactions in osteosarcomas to identify evolutionary links between osteosarcomas. Each layer of our network represents the interactions in one species, and the integrated network captures interactions preserved across species. We perform enrichment analysis on these networks and statistically evaluate differences between the topologies of the regulatory networks of these three species, investigating the functional impact of species-specific interactions and how each affects drug response. Additionally, we survey the literature to identify mutations in osteosarcomas from each species, and calculate diffusion scores for mutated genes in each layer of the network compared to genes mutated in osteosarcoma. As future work, we aim to utilize our comparative genomics approach and leverage the differences between interaction networks of related species to compute the likelihood of identifying early-stage therapeutic trials that will fail in later stages, thus avoiding costly experiments and guiding drug development. Citation Format: Tina Salehi Torabi, Soumya Gottipati, Tamer Kahveci, Kiley Graim. Multi-species regulatory analysis of osteosarcoma to reduce clinical trial failure rates [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A020.
Mendelian randomisation of eosinophils and other cell types in relation to lung function and disease
Authors: Anna Guyatt, Catherine John, Alexander T Williams, Nick Shrine, Nicola F Reeve, Ian Sayers, Ian Hall, Louise V Wain, Nuala Sheehan, Frank Dudbridge, Martin D Tobin
Journal: Thorax (2022)

Eosinophils are associated with airway inflammation in respiratory disease. Eosinophil production and survival is controlled partly by interleukin-5: anti-interleukin-5 agents reduce asthma and response correlates with baseline eosinophil counts. However, whether raised eosinophils are causally related to chronic obstructive pulmonary disease (COPD) and other respiratory phenotypes is not well understood.
Controlled lab experiments are one of many useful scientific methods to investigate bias
Authors: Jason A. Okonofua
Journal: Behavioral and Brain Sciences (2022)

Abstract Ecological validity is key in science and laboratory experiments alone cannot fully explain complex real-world phenomena. Yet the three flaws Cesario proposes do not characterize the field and are not “methodological trickery,” (sect. 5, para. 5) designed to intentionally mislead practitioners. In school discipline alone, these alleged flaws are indeed addressed and laboratory experimentation has contributed to mitigation of a real-world problem.
Krüppel-like factor-4 and Krüppel-like factor-2 are important regulators of joint tissue cells and protect against tissue destruction and inflammation in osteoarthritis
Authors: Manabu Kawata, Takeshi Teramura, Philip Ordoukhanian, Steven R Head, Padmaja Natarajan, Aishwarya Sundaresan, Merissa Olmer, Hiroshi Asahara, Martin K Lotz
Journal: Annals of the Rheumatic Diseases (2022)

Objectives Analysing expression patterns of Krüppel-like factor (KLF) transcription factors in normal and osteoarthritis (OA) human cartilage, and determining functions and mechanisms of KLF4 and KLF2 in joint homoeostasis and OA pathogenesis. Methods Experimental approaches included human joint tissues cells, transgenic mice and mouse OA model with viral KLF4 gene delivery to demonstrate therapeutic benefit in structure and pain improvement. Mechanistic studies applied global gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq). Results Several KLF genes were significantly decreased in OA cartilage. Among them, KLF4 and KLF2 were strong inducers of cartilage collagen genes and Proteoglycan-4. Cartilage-specific deletion of Klf2 in mature mice aggravated severity of experimental OA. Transduction of human chondrocytes with Adenovirus (Ad) expressing KLF4 or KLF2 enhanced expression of major cartilage extracellular matrix (ECM) genes and SRY-box transcription factor-9, and suppressed mediators of inflammation and ECM-degrading enzymes. Ad-KLF4 and Ad-KLF2 enhanced similar protective functions in meniscus cells and synoviocytes, and promoted chondrocytic differentiation of human mesenchymal stem cells. Viral KLF4 delivery into mouse knees reduced severity of OA-associated changes in cartilage, meniscus and synovium, and improved pain behaviours. ChIP-seq analysis suggested that KLF4 directly bound cartilage signature genes. Ras-related protein-1 signalling was the most enriched pathway in KLF4-transduced cells, and its signalling axis was involved in upregulating cartilage ECM genes by KLF4 and KLF2. Conclusions KLF4 and KLF2 may be central transcription factors that increase protective and regenerative functions in joint tissue cells, suggesting that KLF gene transfer or molecules upregulating KLFs are therapeutic candidates for OA.
Concordance and discordance in SLE clinical trial outcome measures: analysis of three anifrolumab phase 2/3 trials
Authors: Ian N Bruce, Richard A Furie, Eric F Morand, Susan Manzi, Yoshiya Tanaka, Kenneth C. Kalunian, Joan T Merrill, Patricia Puzio, Emmanuelle Maho, Christi Kleoudis, Marius Albulescu, Micki Hultquist, Raj Tummala
Journal: Annals of the Rheumatic Diseases (2022)

In the anifrolumab systemic lupus erythematosus (SLE) trial programme, there was one trial (TULIP-1) in which BILAG-based Composite Lupus Assessment (BICLA) responses favoured anifrolumab over placebo, but the SLE Responder Index (SRI(4)) treatment difference was not significant. We investigated the degree of concordance between BICLA and SRI(4) across anifrolumab trials in order to better understand drivers of discrepant SLE trial results.
Diagnostic accuracy of WHO screening criteria to guide lateral-flow lipoarabinomannan testing among HIV-positive inpatients: A systematic review and individual participant data meta-analysis
Authors: Ashar Dhana, Yohhei Hamada, Andre P Kengne, Andrew D Kerkhoff, Tobias Broger, Claudia M Denkinger, Molebogeng X Rangaka, Ankur Gupta-Wright, Katherine Fielding, Robin Wood, Helena Huerga, Sekai Chenai Mathabire Rücker, Stephanie Bjerrum, Isik S Johansen, Swe Swe Thit, Mar Mar Kyi, Josh Hanson, David A Barr, Graeme Meintjes, Gary Maartens
Journal: Journal of Infection (2022)
Biomarker Testing, Treatment Uptake, and Survival Among Patients With Urothelial Cancer Receiving Gene-Targeted Therapy
Authors: Vivek Nimgaonkar, Rebecca A. Hubbard, Erica L. Carpenter, Ronac Mamtani
Journal: JAMA Oncology (2022)

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Evolving epidemiology of pneumocystis pneumonia: Findings from a longitudinal population-based study and a retrospective multi-center study in Germany
Authors: Benedikt Kolbrink, Jubin Scheikholeslami-Sabzewari, Christoph Borzikowsky, Friedrich A. von Samson-Himmelstjerna, Andrew J. Ullmann, Ulrich Kunzendorf, Kevin Schulte
Journal: The Lancet Regional Health - Europe (2022)

Pneumocystis pneumonia (PCP) is a life-threatening opportunistic infectious disease of immunocompromised patients. Its incidence has decreased worldwide in the past, but data concerning its recent epidemiology are lacking.We retrospectively analyzed all German inpatient cases from January 1, 2014 to December 31, 2019, to describe the recent epidemiology, incidence, clinical course, mortality and underlying diseases of PCP. Simultaneously, we conducted a retrospective multi-center study at two German university hospitals, and analyzed PCP cases treated there to gain deeper insights on the basis of primary patient data.The incidence of PCP significantly increased from 2·3 to 2·6 per 100,000 population from 2014 to 2019 (1,857 to 2,172 cases, +17·0%, p < 0·0001), as well as PCP-related deaths (516 to 615 cases, +19·2%, p = 0·011). The spectrum of underlying diseases changed: Risk groups with established chemoprophylaxis for PCP based on international guidelines (HIV, hematologic malignancies, and transplantation) showed a significant decrease in PCP cases and deaths. Others, especially those with solid malignancies, and autoimmune and pulmonary diseases showed a significant increase in case numbers and deaths. Data from the retrospective multi-center study added information regarding prophylaxis and diagnostics of PCP.The incidence of PCP has reversed its trend, showing a significant increase in mortality on population level. Patients who were not previously considered in prophylactic measures are increasingly affected by PCP. This development deserves further investigation, and additional comprehensive guidelines for the use of chemoprophylaxis in new risk groups are needed.Department of Nephrology and Hypertension, University Hospital Schleswig-Holstein, Kiel.
Abstract IA012: Aging, tissue ecology, and the evolution of cancer within us
Authors: James DeGregori, Catherine Pham-Danis, Andrii I Rozhok, Edward J. Evans, Fabio Marongiu, Hannah Scarborough, Curtis J. Henry
Journal: Cancer Research (2022)

Abstract Why do we get cancer? Why is cancer highly associated with old age? Of course, aging is associated with the accumulation of more mutations, and some of these mutations can contribute to cancer phenotypes. But we now understand that carcinogenesis is much more complex than originally appreciated. In particular, there are tissue environmental forces that both impede and promote cancer evolution. Just as organismal evolution is known to be driven by environmental changes, cellular (somatic) evolution in our bodies is similarly driven by changes in tissue environments, whether caused by the normal process of aging, by lifestyle choices or by extrinsic exposures. Environmental change promotes selection for new phenotypes that are adaptive to the new context. In our tissues, aging or insult-driven alterations in tissues drives selection for adaptive mutations, and some of these mutations can confer malignant phenotypes. We have been using mouse models of cancer initiation, mathematical models of cellular evolution, and analyses of human tissue samples to better understand the evolutionary forces that control somatic cell evolution and thus cancer risk. We have shown that aging and inflammation dependent changes in tissue environments dramatically dictate whether cancer-causing mutations are advantageous to stem cells in our tissues, starting the cells down the path to cancer. Our studies have focused on cancer initiation within the hematopoietic system and the lung. These studies have also uncovered molecular explanations for mutation-driven adaptation to aged and inflammatory tissue environments. In all, these studies indicate that strategies to prevent or treat cancers will need to incorporate interventions that alter tissue microenvironments. Citation Format: James DeGregori, Catherine Pham-Danis, Andrii I Rozhok, Edward J. Evans, Fabio Marongiu, Hannah Scarborough, Curtis J. Henry. Aging, tissue ecology, and the evolution of cancer within us [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA012.
Ventricular-Arterial Coupling Derived From Proximal Aortic Stiffness and Aerobic Capacity Across the Heart Failure Spectrum
Authors: Nicola Riccardo Pugliese, Alessio Balletti, Silvia Armenia, Nicolò De Biase, Francesco Faita, Alessandro Mengozzi, Francesco Paneni, Frank Ruschitzka, Agostino Virdis, Lorenzo Ghiadoni, Stefano Taddei, Bryan Williams, Francesco Antonini-Canterin, Stefano Masi
Journal: JACC. Cardiovascular imaging (2022)
Multifunctional nanoparticles of sinomenine hydrochloride for treat-to-target therapy of rheumatoid arthritis via modulation of proinflammatory cytokines
Authors: Ye Lin, Ouyang Yi, Mingyue Hu, Shengtao Hu, Zhaoli Su, Jin Liao, Wei Wang, Shenzhi Wang, Liang Liu, Bin Liu, Xiong Cai
Journal: Journal of Controlled Release (2022)
Ischemic colitis after COVID-19 mRNA vaccine
Authors: Klaus Mönkemüller, Elnura Abdullayeva, Kiril Manovski, Miguel Cacho-Díaz
Journal: Endoscopy (2022)

An 82-year-old woman with a history of hypertension and osteoarthritis was admitted with abdominal pain and hematochezia that developed 7 days after she had received her second COVID-19 mRNA vaccination (BioNTech, Germany). Severe lower abdominal tenderness was present with decreased bowel sounds. Abnormal laboratory findings were leukocytosis (18 000/µL; normal 4500–10 500/µL) and increased C-reactive protein (50 mg/dL; normal < 5 mg/dL). Abdominal ultrasound revealed massive edema of the colon but no atherosclerosis of the aorta or narrowing of the pelvic arteries. Sigmoidoscopy revealed deep ulcers, luminal narrowing, and frank mucosal necrosis starting at the rectosigmoid and extending into the entire sigmoid colon ([Video 1], [Fig. 1]). Additional extensive evaluation including stool cultures and studies for viral and autoimmune diseases did not reveal any other cause for the ischemic colitis. Histology showed frank necrosis with lymphocytic infiltration of the lamina propria, in addition to occluded vessels with inflammatory infiltrates, without eosinophilia or pseudomembranes. The patient was treated with intravenous fluids and metronidazole for 5 days. Her symptoms slowly subsided and she was discharged home on day 7. The temporal relationship, in the absence of any other inciting factors, medications, or abnormal anatomic vessel abnormalities, suggests that the causative event for the ischemic colitis was the mRNA vaccination. The SARS-CoV-2 spike is a key pathogenic factor of this novel coronavirus, allowing the virion to attach itself to the cells and then deliver its genetic contents inside the cytoplasm [1]. Some COVID-19 vaccines are a form of genetic therapy that use nanoparticles carrying mRNA to transfect the cell introducing the genetic material encoding the S-spike inside. SARS-CoV-2 spike protein dysregulates prothrombin and fibrinogen chains [2]. The S-spike also phosphorylates ACE2, leading to MAPK signaling activation with phosphorylation of Erk, p-38, and JNK and subsequent platelet activation, release of coagulation factors, and secretion of inflammatory cytokines [2]. This inflammatory state may further enhance the thrombophilia per se or in the setting of vaccine-induced thrombocytopenia, autoimmune vasculitis or result in arterial or venous thrombosis in different parts of the body.
Clinical relevance of biomarkers in cholangiocarcinoma: critical revision and future directions
Authors: Rocio I R Macias, Vincenzo Cardinale, Timothy J Kendall, Matias A Avila, Maria Guido, Cedric Coulouarn, Chiara Braconi, Adam E Frampton, John Bridgewater, Diletta Overi, Stephen P Pereira, Marco Rengo, Jakob N Kather, Angela Lamarca, Federica Pedica, Alejandro Forner, Juan W Valle, Eugenio Gaudio, Domenico Alvaro, Jesus M Banales, Guido Carpino
Journal: Gut (2022)

Cholangiocarcinoma (CCA) is a malignant tumour arising from the biliary system. In Europe, this tumour frequently presents as a sporadic cancer in patients without defined risk factors and is usually diagnosed at advanced stages with a consequent poor prognosis. Therefore, the identification of biomarkers represents an utmost need for patients with CCA. Numerous studies proposed a wide spectrum of biomarkers at tissue and molecular levels. With the present paper, a multidisciplinary group of experts within the European Network for the Study of Cholangiocarcinoma discusses the clinical role of tissue biomarkers and provides a selection based on their current relevance and potential applications in the framework of CCA. Recent advances are proposed by dividing biomarkers based on their potential role in diagnosis, prognosis and therapy response. Limitations of current biomarkers are also identified, together with specific promising areas (ie, artificial intelligence, patient-derived organoids, targeted therapy) where research should be focused to develop future biomarkers.
Abstract B013: Dissecting cell states that enable multi-stressor resistance in cancer
Authors: Dylan L. Schaff, Aria J. Fasse, Sydney M. Shaffer
Journal: Cancer Research (2022)

Abstract In this work, we investigate how single-cell differences in melanoma lead to resistance to multiple diverse and therapeutically relevant stressors. Targeted small-molecule inhibitors and immunotherapy have shown incredible success in the clinic. However, most patients still only partially respond to a given treatment, succumbing to recurrent, treatment-resistant tumors. As a result, oncologists must resort to sequentially treating tumors with new drugs or co-treating with multiple drugs from the beginning. Despite such a complex clinical paradigm, researchers are still studying the root of treatment resistance one drug at a time. We believe that by more broadly studying how certain cells adapt to and survive a multitude of stressful conditions, we can identify treatment strategies that more effectively overcome many resistant behaviors at once. Here, we use lentiviral cell barcoding to simultaneously trace cells that survive stress from microenvironmental factors (extracellular acidosis and hypoxia), inhibition of specific signaling pathways (with Dabrafenib and Trametinib), and chemotherapy (Cisplatin and Doxorubicin) back to their cells of origin and characterize them by scRNA-seq. Strikingly, we have found that there is a rare population of stress-naïve cells that is resistant to our entire panel of stressors. We are exploring two complementary approaches for overcoming this multi-stressor resistance. First, we have combined cell barcoding and scRNA-seq to identify the initial differences in gene expression that allow certain lineages of cells to survive across stressful conditions. Our goal is to use small-molecule inhibitors and genetic knockouts to target these differences in gene expression in stress-naïve cells, eliminating multi-stressor resistance at its source. Second, we are tracking lineages of cells as they undergo a series of cellular changes needed to ultimately survive our panel of stressors. Using scRNA-seq and cell barcoding, we are identifying these crucial changes as cells reprogram into full resistance. We will look to prevent this reprogramming by simultaneously stressing cells and targeting core reprogramming genes and pathways. Overall, this work uncovers single-cell gene expression differences that allow cancer cells to survive under many stressful conditions. We will work to overcome this resistance by directly eliminating the multi-stressor resistant cells and disrupting their ability to reprogram. Citation Format: Dylan L. Schaff, Aria J. Fasse, Sydney M. Shaffer. Dissecting cell states that enable multi-stressor resistance in cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B013.
Aerosolization of <i>Mycobacterium tuberculosis</i> by Tidal Breathing
Authors: Ryan Dinkele, Sophia Gessner, Andrea McKerry, Bryan Leonard, Juane Leukes, Ronnett Seldon, Digby F. Warner, Robin Wood
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

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